PROJECT SUMMARY The development of safe and effective medications for the treatment of alcohol use disorders (AUDs) is a public health priority. Stress and mood are significant components of relapse in addiction, including alcohol dependence. The kappa opioid receptor (KOR) system plays a role in relapse to substance use and KOR antagonism has the potential to play an important role in the treatment of mood and substance use disorders. CERC-501 is an oral, once daily, highly specific and bioavailable KOR antagonist that reduces the EtOH preference behaviors of P-preferring rats, alleviates nicotine withdrawal syndrome in mice, and reduces depression- and anxiety- behaviors in animal models. CERC-501 was well tolerated in the three completed Phase 1 human studies (SAD, MAD and PET study). The primary objectives of the proposal are to enable pre-IND activities, file an IND for a new formulation and complete a pharmacokinetic and safety study of the new formulation. The pre-IND activities include development of new enteric coated formulation (CERC-501 EC) designed for maximal dispersion and release in the small intestine, bypassing the stomach. Cerecor will conduct a repeat-dose range-finding study, 6-month safety study with CERC-501 EC in minipigs and file an IND with FDA's DAAAP for the treatment of AUDs. Cerecor will conduct a pharmacokinetic (PK) study in healthy humans that will assess the bioavailability and PK profile of the CERC-501 EC, compare systemic exposure of CERC-501 EC to the current formulation and assess if food impacts bioavailability. Lastly, Cerecor will conduct a 9-month toxicology study with CERC-501 in dogs, so as to conclude the toxicology program that is required to support administration longer than 6 months in patients. Cerecor plans to register CERC-501 EC as new pharmacotherapy for AUDs. CERC-501 EC will be indicated for the maintenance of abstinence from alcohol and reduction in heavy drinking days in patients who are abstinent at treatment initiation and ii) for the reduction of heavy drinking in patients who are actively drinking at treatment initiation. After initial registration for treatment of AUD is completed clinical studies in co-occurring disorders, AUD and depression will be conducted.